Cutting edge discoveries are demonstrating that tiny snippets of double strand RNA can interrupt gene transcription by cleaving the target complementary matched mRNA, and consequently inhibit expression of the protein that is encoded by the gene. The discovered phenomena, termed RNA interference (RNAi), possesses practical applications to be used for medicine, for example, by inactivating genes that cause disease. Periodontal disease is characterized by chronic inflammation associated with multiple bacterial infections in the crevice between gingiva and tooth, resulting in soft tissue destruction and bone resorption. Currently, a key molecular mechanism underlying bone resorption was elucidated by the discovery of osteoclast differentiation cytokine, RANKL (Receptor Activator of NF-kappaB Ligand) that plays a pivotal role on bone loss in many, including osteoporosis, rheumatoid arthritis and periodontal disease. Our group has established the rat periodontal disease model that causes T cell-mediated bone resorption in RANKL dependent manner, as well as in vitro assay system to analyze RANKL-induced osteoclastogenesis. The working hypothesis is that RNAi based gene-silencing targeting on the RANKL signaling pathway can ameliorate bone resorption induced in the rat periodontal disease model. The future goal of this work is to develop a clinical therapy to target the bone resorption process in periodontal disease by RNAi based gene therapy.